The default mode network (DMN) is a major resting-state network that supports most of the baseline brain activity. Recent studies revealed that DMN cortical hub regions, including the medial prefrontal cortex, parietal cortex, posterior cingulum, and precuneus are all affected early during Alzheimer’s disease (AD) and exhibit high amounts of Aβ deposits. The cells generating Aβ are chiefly cortical and some brainstem projection neurons. Because processing of the amyloid precursor protein is activity-dependent, it can be speculated that due to their constant activity, DMN neurons produce and release more Aβ than occurs elsewhere in the neocortex, thus leading to an increase in production, oligomerization and aggregation of Aβ as well as tau hyperphosphorylation, which presumably is caused by the released Aβ oligomers. DMN cortical regions are richly innervated by long projection fibers from the noradrenergic locus coeruleus (LC), the serotonergic dorsal raphe nucleus (DRN), as well as the cholinergic basal forebrain (nucleus basalis complex, NB), which all may release high amounts of Aβ in the vicinity of glutamatergic projection neurons in the DMN cortical regions that are vulnerable to tau pathology and neurofibrillary degeneration. Recent findings provide converging evidence that the amyloid accumulation and DMN functional alterations are closely linked with the changes of sleep-wake cycle (particularly in regard of lesser amount of short-wave deep sleep when metabolic demands are about 50% lower in comparison with awake state and when presumably less amyloid is produced) and pre-tangle changes of LC, thus opening new promising area for future research.

Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.

Understanding the intra-and extracellular proteins involved in the development of the corticospinal tract (CST) may offer insights into how the pathway could be regenerated following traumatic spinal cord injury. Currently, however, little is known about the proteome of the developing corticospinal system. The present study, therefore, has used quantitative proteomics and bioinformatics to detail the protein profile of the rat CST during its formation in the spinal cord. This analysis identified increased expression of 65 proteins during the early ingrowth of corticospinal axons into the spinal cord, and 36 proteins at the period of heightened CST growth. A majority of these proteins were involved in cellular assembly and organisation, with annotations being most highly associated with cytoskeletal organisation, microtubule dynamics, neurite outgrowth, and the formation, polymerisation and quantity of microtubules. In addition, 22 proteins were more highly expressed within the developing CST in comparison to other developing white matter tracts of the spinal cord of age-matched animals. Of these differentially expressed proteins, only one, stathmin 1 (a protein known to be involved in microtubule dynamics), was both highly enriched in the developing CST and relatively sparse in

Amyloid β1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) are the main cerebrospinal fluid (CSF) biomarkers for early diagnosis of Alzheimer’s disease (AD). Detection of AD is critically important in view of the growing number of potential new drugs that may influence the course of the disease in its early phases. However, cut-off levels for these CSF biomarkers have not yet been established. Variability in absolute concentrations of AD biomarkers is high among studies and significant differences were noticed even within the same datasets. Variability in biomarkers levels in these assays may be due to many aspects of operating procedures. Standardization of pre-analytical and analytical procedures in collection, treatment, and storage of CSF samples is crucial because differences in sample handling can drastically influence results. Multicenter studies showed that usage of ELISA kits from different manufacturers also affects outcome. So far only very few studies tested the efficiency of ELISA kits produced by different vendors. In this study, the performance of Innogenetics (Gent, Belgium) and Invitrogen (Camarillo, CA, USA) ELISA kits for t-tau and Aβ1-42 was tested. Passing-Bablok analysis showed significant differences between Invitrogen and Innogenetics ELISA methods, making it impossible to use them interchangeably.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposits of β amyloid peptides (Aβ) in senile plaques, and intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles (NFT). Although accumulation of Aβ has been long considered a leading hypothesis in the disease pathology, it is increasingly evident that the role hyperphosphorylation of tau in destabilization of microtubule assembly and disturbance of axonal transport is equally detrimental in the neurodegenerative process. The main kinase involved in phosphorylation of tau is glycogen-synthase kinase 3-beta (GSK-3β). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated tau by a mechanism dependent on GSK-3β. In addition, Aβ affects production of ceramides, the major sphingolipids in mammalian cells, by acting on sphingomyelinases, enzymes responsible for the catabolic formation of ceramides from the sphingomyelin. Generated ceramides in turn increase production of Aβ by acting on β-secretase, a key enzyme in the proteolytic processing of the amyloid precursor protein (APP), altogether leading to a ceramide-Aβ-hyperphosphorylated tau cascade that ends in neuronal death. Modulators and inhibitors acting on members of this devastating cascade are considered as potential targets for AD therapy. There is still no adequate treatment for AD patients. Novel therapeutic strategies increasingly consider the combination of multiple targets and interactions among the key members of implicated molecular pathways. This review summarizes recent findings and therapeutic perspectives in the pathology and treatment of AD, with the emphasis on the interplay between hyperphosphorylated tau, amyloid β, and sphingolipid mediators.